ABSTRACT Our previous studies demonstrated that young adult mice lacking the superoxide anion scavenger CuZnSOD (Sod1KO mice) exhibit age-related muscle atrophy/weakness that closely mimics the sarcopenia phenotype of old wild type mice, including NMJ degeneration, retraction of motor neurons and elevated muscle mitochondrial ROS (mtROS) generation and calcium levels. Replacing CuZnSOD specifically in the motor neurons in Sod1KO mice reverses muscle atrophy and weakness, NMJ disruption and muscle oxidative stress, suggesting that motor neuron deficits are likely the initiating event in sarcopenia in the Sod1KO mice. However, both neuronal specific Sod1 knockout (nSod1KO) mice and muscle specific Sod1 knockout (mSod1KO) mice show a loss in contractile force in the gastrocnemius that is not associated with loss of muscle mass. Thus, deletion of Sod1 and induction of oxidative stress in either neurons or skeletal muscle ALONE does not replicate the full sarcopenia phenotype of the Sod1KO mice, suggesting that sarcopenia results from an interactive effect between the two tissues. Here we will test the hypothesis that pre-synaptic deficits initiate altered NMJ structure and function that further requires increased mtROS and/or altered calcium homeostasis in muscle to generate the sarcopenia phenotype. First, we will measure the comprehensive phenotype of the nSod1KO mice compared to mice with a combined deletion of Sod1 in muscle and neurons (nSod1KO x mSod1KO mice) on the elevation in oxidative stress and the cascade of pre- and postsynaptic events involved in sarcopenia. This will allow us to determine the impact of neuronal deficits on downstream processes in sarcopenia and definitively determine whether both muscle and neuron are necessary for the development of the sarcopenia phenotype observed in the Sod1KO mice. Next, using conditional knockout models, we will test whether elevated muscle mitochondrial ROS in muscle specific MnSOD knockout (mSod2KO) mice is sufficient to induce sarcopenia without presynaptic initiation of NMJ disruption. Conversely, we will determine the importance of muscle oxidative stress in the induction of sarcopenia by determining whether elevated motor neuron oxidative stress present in the constitutive Sod1KO mouse is sufficient to induce sarcopenia when muscle oxidative stress is reduced by expression of mitochondrial catalase. In each model, we will measure presynaptic changes in motor neuron structure and function, changes in NMJ structure and function, downstream changes in muscle mtROS and calcium signaling and changes in muscle force and mass. These studies will definitively show whether neuronal initiation of NMJ disruption is sufficient for muscle atrophy/weakness or if additional alterations in muscle oxidative stress are required to induce the phenotype.